Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems

Definitions

• WO 89/10369 generically discloses compounds which can have the structure: wherein Z can be O and R can be: wherein Y can be NR11 and R11 can be -O-; however, no specific compounds are disclosed with this structure.
• WO 88/03138 discloses compounds of the formula or a pharmaceutically acceptable salt or solvate thereof, wherein: one of a, b, c and d represents N or NR9 where R9 is O -CH3 or -(CH2) n CO2H where n is 1 to 3, and the remaining a, b, c and d groups are CH, which remaining a, b, c and d groups optionally may be substituted with R1 or R2; R1 and R2 may be the same or different and each independently represents halo, -CF3, -OR10, -COR10, -SR10, -N(R10)2, -NO2, -OC(O)R10, -CO2R10, -OCO2R11, alkynyl, alkenyl or alkyl, which alkyl
• WO 90/13548 published on November 15, 1990 on PCT/US90/02251 which was filed on April 30, 1990 and claims priority to U.S. Application Serial No. 345,604 filed May 1, 1989 discloses compounds similar in structure to the compounds disclosed in WO 88/03138 with the difference being that the R group represents an N-oxide heterocyclic group of the formula (i), (ii), (iii), or (iv): wherein R9, R10, and R11 can be, amongst other groups, H.
• any of R1, R2, R3 and R4 may be the same or different from each other and each independently represents a hydrogen atom or other substituent;
• X represents an aralkyl- or aryl-containing group having from 6 to 30 carbon atoms or an alkyl group having from 4 to 30 carbon atoms or a cycloalkyl-containing group, which may optionally have substituent(s) and which may be substituted by hetero atom(s) or hetero atom-containing organic group(s) said alkyl group optionally containing unsaturated bond(s);
• Y represents a heteroatom or an optionally substituted alkylene chain, the alkylene chain optionally containing hetero atom(s) or unsaturated bond(s); and
• A represents an optionally substituted condensed aromatic or
• European Patent Publication No. 0 371 805 also discloses that if present, the aromatic ring of X or A is benzene, pyridine, pyridazine, or pyrazine, amongst others (see page 3 at about lines 35-40).
• This invention provides compounds represented by Formula I: or a pharmaceutically acceptable salt or solvate thereof, wherein: R represents H or a halogen atom selected from the group consisting of: Cl, Br, F, and I; T represents C or N with the dotted line attached to T representing a double bond when T is C and being absent when T is N; and X represents O or S with the proviso that T is N when X is O.
• R represents H or a halogen atom selected from the group consisting of: Cl, Br, F, and I
• T represents C or N with the dotted line attached to T representing a double bond when T is C and being absent when T is N
• X represents O or S with the proviso that T is N when X is O.
• One preferred embodiment of this invention provides compounds of Formula IA: wherein R is as defined for Formula I, and most preferably R is Cl.
• Another preferred embodiment of this invention provides compounds of Formula IB: wherein X and R are as defined for Formula I, and most preferably R is Cl.
• Representative compounds of this invention include :
• N-oxide heterocyclic ring may be equally represented as:
• This invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound represented by Formula I and a pharmaceutically acceptable carrier.
• This invention further provides a method of treating asthma, allergy and/or inflammation in a mammal, preferably a human, in need of such treatment, said method comprising administering an anti-asthmatic, anti-allergic and/or anti-inflammatory effective amount, respectively, of a compound of Formula I.
• a mammal preferably a human
• the compound is administered as a pharmaceutical composition of this invention.
• Certain compounds of this invention may exist in different isomeric (e.g., enantiomers and diastereoisomers) as well as conformational forms. This invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures.
• the compounds of the invention of Formula I can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., hemihydrate.
• solvated forms including hydrated forms, e.g., hemihydrate.
• pharmaceutically acceptable solvents such as water, ethanol and the like, are equivalent to the unsolvated forms for purposes of this invention.
• Compounds of this invention are basic in nature, i.e., all compounds possess a pyridine ring and in some cases a piperazine ring. Hence, they may form pharmaceutically acceptable salts, e.g., acid addition salts.
• the pyrido-nitrogen atom may form salts with strong acid.
• suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, fumaric, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art.
• the salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner.
• the free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate.
• a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate.
• the free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of this invention.
• a compound of Formula II can be coupled with isonicotinic acid N-oxide in the presence of a coupling agent, such as 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (DEC), N,N′-dicyclohexylcarbodiimide (DCC) or N,N′-carbonyl diimidazole (CDI), to produce compounds of Formula I:
• DEC 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride
• DCC N,N′-dicyclohexylcarbodiimide
• CDI N,N′-carbonyl diimidazole
• the reaction is usually conducted in an inert solvent, such as tetrahydrofuran or methylene chloride, at a temperature between 0°C and reflux, usually at room temperature.
• the coupling agent is DCC or DEC
• the reaction is preferably run in the presence
• a compound of Formula II may also be reacted with a compound of Formula III in the presence of a base to produce compounds of Formula I:
• bases are pyridine and triethylamine.
• L designates a suitable leaving group.
• a compound of Formula III may be an acyl halide (e.g., L is Cl), in which case compound III can be generated from the corresponding carboxylic acid using oxalyl chloride or similar agent.
• Compounds of Formula I may also be prepared by reacting a compound of Formula IV with a compound of Formula III: Preferably this reaction may be run in the presence of a suitable nucleophile (e.g., LiI, and the like) in an inert solvent (e.g., toluene, dioxane or xylenes).
• a suitable nucleophile e.g., LiI, and the like
• an inert solvent e.g., toluene, dioxane or xylenes
• a suitable base such as triethylamine or potassium carbonate may be added, and heating may usually be required.
• a temperature ranging from about 50 to about 150°C (preferably about 100 to about 120°C) may be utilized depending on the boiling point of the solvent.
• Certain compounds of Formula IB may also be prepared by alkylation of a compound of Formula VI with a compound of Formula V.
• the reaction may be conducted in an inert solvent such as tetrahydrofuran or toluene, typically at a temperature range of ambient to reflux depending on the solvent of choice.
• a suitable base may be added such as triethylamine or potassium carbonate, although the reaction may proceed without the addition of base.
• An alternative route for generating a compound of Formula IB may be by reductive amination of compound VII with a compound of the formula VI:
• the reaction may be carried out in a polar solvent such as an alcohol (e.g., methanol or ethanol) and optionally in the presence of a water scavenger such as 3 ⁇ molecular sieves.
• a reducing agent such as NaCNBH3 or H2/Pd-C is necessary for reduction of the intermediate Schiff base.
• Temperatures for the reaction are typically held between 0-100°C depending on the solvent employed.
• Compounds of the general Formula IIA can be prepared by cleaving a carbamate group (COOR′ wherein R′ is an alkyl group, such as ethyl, or an aryl group, such as phenyl) from the corresponding carbamates of Formula VIII. This can be accomplished by a variety of methods including acid hydrolysis (e.g., HCl) or base hydrolysis (e.g., KOH) as long as R′ is a group which does not prevent the cleavage reaction.
• acid hydrolysis e.g., HCl
• base hydrolysis e.g., KOH
• a compound of Formula VIII may be treated with an organometallic reagent (e.g., CH3Li wherein R′ is an alkyl group such as ethyl) or a reductive reagent (e.g., Zn in acid where R′ is 2,2,2-trichloroethyl) in order to produce a compound of Formula IIA.
• organometallic reagent e.g., CH3Li wherein R′ is an alkyl group such as ethyl
• a reductive reagent e.g., Zn in acid where R′ is 2,2,2-trichloroethyl
• Compounds of Formula VIII can be prepared from the corresponding N-methyl compounds of Formula IVA by treating compounds of Formula IVA with a suitable chlorocarbamate containing R′ (e.g., ClCOOR′).
• a suitable chlorocarbamate containing R′ e.g., ClCOOR′
• the reaction can usually be carried out at an elevated temperature (e.g., about 70 to about 100°C) by heating a compound of Formula IVA in an inert solvent, such as toluene, in the presence of the chlorocarbamate and optionally with a base such as triethylamine.
• an inert solvent such as toluene
• Compounds of Formula IVA can be prepared from a corresponding alcohol of Formula XI by using either acidic or basic conditions in accordance with methods well known in the art. For example, treatment of a compound of Formula XI with trifluoromethanesulfonic acid and heating (about 40 to about 60°C) results in dehydration of the alcohol to produce the olefin of Formula IVA.
• Other acids such as polyphosphoric acid or sulfuric acid may also be employed.
• the alcohol of Formula XI can be prepared via the treatment of a ketone of Formula VIIA with the Grignard reagent derived from N-methyl-4-chloropiperidine in an inert solvent such as tetrahydrofuran.
• an inert solvent such as tetrahydrofuran.
• Other organometallic reagents known in the art may also be used; for example, N-methyl-4-lithiopiperidine.
• the reaction may be conducted at or below room temperature (e.g., about -15 to about 25°C); however, the reaction mixture may be refluxed if necessary. Quenching the reaction with a mild acid (such as aqueous ammonium chloride) or water produces an alcohol of Formula XI.
• the Grignard reagent may be prepared from the corresponding halo derivative using methods well known in the art.
• the reaction can be conducted in an inert solvent such as tetrahydrofuran or toluene, typically at a temperature range of ambient to reflux depending on the solvent of choice.
• the piperazine derivative XII is often employed in excess although this is not necessary.
• a suitable base may be added such as triethylamine or potassium carbonate, although the reaction may proceed without it.
• R ⁇ hydrogen
• R ⁇ is a carbamate
• the carbamate must be subsequently removed in order to provide a compound of Formula IIB. This is accomplished in the same manner as described above for the conversion of compound VIII to compound IIA.
• a compound of the Formula XIII may be prepared from a compound XII by reductive amination of compound VII:
• the reaction is typically carried out in a polar solvent such as an alcohol (e.g., methanol or ethanol), optionally in the presence of a water scavenger such as 3 ⁇ molecular sieves.
• a reducing agent such as NaCNBH3 or H2/Pd-C is necessary for reduction of the intermediate Schiff base.
• Temperatures for the reaction are typically held between 0-100°C depending on the solvent employed.
• R ⁇ is a carbamate, then the carbamate must be subsequently removed in order to provide a compound of Formula IIB. This is accomplished in the same manner as described above for the conversion of compound VIII to compound IIA.
• Compound V may be prepared from the corresponding alcohol XIV.
• the alcohol XIV in turn may be obtained from the corresponding ketone VII via a variety of reductive methods.
• various reducing agents such as lithium aluminum hydride, sodium borohydride, lithium and the like, may be used for this conversion.
• the choice of solvent and temperature of the reaction mixture usually depends on the reducing agent employed and the selection of the appropriate conditions is well within the capabilities of those skilled in the art.
• ketones of Formula VII can be prepared via an intramolecular cyclization of the corresponding nitrile of Formula XV. This transformation may be accomplished using a strong acid, such as trifluoromethanesulfonic acid. A wide range temperatures may be employed, for example, about -15 to about 100°C. The addition of water or aqueous acid to the reaction mixture is necessary following the cyclization in order to effect hydrolysis of the resultant imine to the corresponding ketone of Formula VII. Alternatively, an intramolecular Friedel-Crafts acylation of the acid chloride of Formula XVI may also provide the desired ketone of formula VII.
• the reaction may be carried out under usual Friedel-Crafts conditions in an inert solvent and in the presence of a Lewis acid such as aluminum chloride.
• the necessary acid chloride of Formula XVI may be obtained from the nitrile of Formula XV by the nitrile's hydrolysis to the corresponding carboxylic acid with aqueous acid (e.g., aqueous hydrochloric acid with heating) followed by its conversion to the acid chloride of Formula XVI by standard conditions (e.g., thionyl chloride or oxalyl chloride) well known to those skilled in the art.
• Compounds of Formula XV can generally be prepared by reaction of an alkyl halide of Formula XVII (wherein L is a suitable leaving group) with a compound of Formula XVIII.
• a compound of Formula XVIII Those skilled in the art will appreciate that these displacements may be conducted at a variety of temperatures (usually between room temperature and 100°C) in the presence of a base and a suitable polar solvent.
• bases include cesium carbonate (wherein acetone may be used as the polar solvent) or sodium hydride (wherein tetrahydrofuran may be used as the polar solvent).
• L is a hydroxyl group in the compound of Formula XVII and X is an oxygen in the compound of Formula XVIII
• these compounds may be coupled using known in the art Mitsunobe conditions.
• the compounds of Formulas XVII and XVIII may be coupled to produce a compound of Formula XV, where X is oxygen, using triphenylphosphine and diethyl azadicarboxylate in and inert dry solvent such as tetrahydrofuran.
• the reaction may usually be conducted at or below 0°C (e.g., about -15 to about 0°C); however, the reaction may also be heated to reflux.
• the required alkyl halide of Formula XVII (X is halogen) can be obtained from the corresponding 3-methyl-2-cyanopyridine of Formula XIX.
• an inert solvent such as carbon tetrachloride
• an initiator such as aza(bis)isobutyronitrile (ABIN), and heat (T > 50°C) or light.
• a compound of Formula XVII, wherein X is a hydroxyl group may be obtained from the corresponding carboxylic acid of Formula XX using reductive conditions which do not result in reduction of the cyano group (e.g., diborane in tetrahydrofuran) as is well known in the art.
• Compounds of the Formula XXI can be prepared by coupling a compound of the Formula III with a compound of the Formula XII. This can be accomplished using a coupling agent such as DEC wherein L of compound III is a hydroxyl group or by direct acylation in the presence of base when L of compound III is a good leaving group, such as when L is halogen.
• a coupling agent such as DEC wherein L of compound III is a hydroxyl group or by direct acylation in the presence of base when L of compound III is a good leaving group, such as when L is halogen.
• R ⁇ is hydrogen then compound XXI is the same as compound VI. However, if R ⁇ is a carbamate then the carbamate must be subsequently removed in order to provide compound VI. This is accomplished in the same manner as described above for the conversion of compound VIII to compound IIA.
• the compounds of the invention possess platelet-activating factor ("PAF") antagonistic properties.
• PAF platelet-activating factor
• the compounds of the invention are, therefore, useful when PAF is a factor in the disease or disorder.
• PAF is an important mediator of such processes as platelet aggregation, smooth muscle contraction (especially in lung tissue), vascular permeability and neutrophil activation. Recent evidence implicates PAF as an underlying factor involved in airway hyperreactivity.
• the PAF antagonistic properties of these compounds may be demonstrated by use of standard pharmacological testing procedures as described below. These test procedures are standard tests used to determine PAF antagonistic activity and to evaluate the usefulness of said compounds for counteracting the biological effects of PAF.
• the in vitro assay is a simple screening test, while the in vivo test mimics clinical use of PAF antagonists to provide data which simulates clinical use of the compounds described herein.
• Platelet-activating factor causes aggregation of platelets by a receptor-mediated mechanism. Therefore, PAF-induced platelet aggregation provides a simple and convenient assay to screen compounds for PAF antagonism.
• Human blood 50 mL was collected from healthy male donors in an anticoagulant solution (5 mL) containing sodium citrate (3.8%) and dextrose (2%). Blood was centrifuged at 110 x g for 15 min. and the supernatant platelet-rich plasma (PRP) carefully transferred into a polypropylene tube. Platelet-poor-plasma (PPP) was prepared by centrifuging PRP at 12,000 x g for 2 min. (Beckman Microfuge B). PRP was used within 3 hr. of drawing the blood.
• BSA bovine serum albumen
• Collagen (Sigma) and adenosine diphosphate (ADP) (Sigma) were purchased as solutions. Test compounds were initially dissolved in dimethyl sulfoxide (DMSO) at a concentration of 50 mM and then further diluted in Hepessaline-BSA buffer to achieve appropriate concentrations.
• DMSO dimethyl sulfoxide
• the aggregatory response was kept within a set limit by varying the concentration of PAF. Incubations were continued until the increase in light transmission reached a maximum (usually 2 min.). This increase in light transmission reflecting platlet aggregation is transmitted to a computer by the Chrono-Log model 810 AGGRO/LINK interface.
• the AGGRO/LINK calculates the slope of transmission change, thus providing the rate of aggregation. values for inhibition were calculated by comparing rates of aggregation obtained in the absence and the presence of the compound.
• a standard PAF antagonist such as 8-chloro-6,11-dihydro-11-(1-acetyl-4-piperidylidene)-5 H -benzo[5,6]cyclohepta[1,2-b]pyridine was used as a positive control.
• mice Male Hartley guinea pigs (450-550 g) were obtained from Charles River Breeding Laboratories. The animals were fasted overnight and the following day were anesthetized with 0.9 mL/kg i.p. of dialurethane (containing 0.1 g/mL diallylbarbituric acid, 0.4 g/mL ethylurea and 0.4 g/mL urethane). The left jugular vein was cannulated for the administration of compounds. The trachea was cannulated and the animals were ventilated by a rodent respirator at 55 strokes/min. With a stroke volume of 4 mL.
• dialurethane containing 0.1 g/mL diallylbarbituric acid, 0.4 g/mL ethylurea and 0.4 g/mL urethane.
• the left jugular vein was cannulated for the administration of compounds.
• the trachea was cannulated and the
• a side arm to the tracheal cannula was connected to a pressure transducer to obtain a continuous measure of inflation pressure. Bronchoconstriction was measured as the percent increase in inflation pressure that peaked within 5 min. after challenge with spasmogen.
• the animals were challenged i.v. With either histamine (10 ug/kg) or PAF (0.4 ⁇ g/kg in isotonic saline containing 0.25% BSA). Each animal was challenged with only a single spasmogen. The effect of a compound on the bronchospasm is expressed as a percent inhibition of the increase in inflation pressure compared to the increase in a control group. Results are shown in Table 1 below.
• Table 1 demonstrate that the compounds of this invention (e.g., Compound Numbers 3 - 5 in Table 1) are much more selective in their antagonism of PAF (i.e., they are weak antihistamines) than previous compounds of this structural type.
• Compounds 3 - 5 are active against the PAF response at a dose of 1 mg/kg orally, but even at higher doses (3 - 10 mg/kg) Compounds 3 - 5 have no effect on the response to histamine. This contrasts with Compounds 1 and 2 where there is an effect on both responses at similar doses.
• inert, pharmaceutically acceptable carriers can be either solid or liquid.
• Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
• the powders and tablets may be comprised of from about 5 to about 70 percent active ingredient.
• Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.
• a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.
• Liquid form preparations include solutions, suspensions and emulsions. As an example there may be mentioned water or water-propylene glycol solutions for parenteral injection.
• Liquid form preparations may also include solutions for intranasal administration.
• Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas.
• a pharmaceutically acceptable carrier such as an inert compressed gas.
• solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
• liquid forms include solutions, suspensions and emulsions.
• the compounds of the invention may also be deliverable transdermally.
• the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
• the compound is administered orally.
• the pharmaceutical preparation is in unit dosage form.
• the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
• the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.1 mg to 1000 mg, more preferably from about 1 mg. to 500 mg, according to the particular application.
• the appropriate dosage can be determined by comparing the activity of the compound with the activity of a known antihistaminic compound such as 8-chloro-6,11-dihydro-11-(1-ethoxycarbonyl-4-piperidylidene)-5 H -benzo[5,6]cyclohepta[1,2-b]pyridine, which compound is disclosed in U.S. Patent No. 4,282,233.
• the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
• a typical recommended dosage regimen is oral administration of from 10 mg to 1500 mg/day, preferably 10 to 750 mg/day, in two to four divided doses to achieve relief of the symptoms.
• the compounds are non-toxic when administered within this dosage range.
• compositions which may contain a compound of the invention.
• active compound is used to designate the compound 4-(8-chloro-5,11-dihydro[1]benzothiepino[4,3-b]pyridin-11-ylidene)-1-(4-pyridinylcarbonyl)piperidine N1-oxide.
• the scope of the invention in its pharmaceutical composition aspect is not to be limited by the examples provided, since any other compound of structural Formula I can be substituted into the pharmaceutical composition examples.

Applications Claiming Priority (2)

Publications (1)

Family

ID=24951610

Family Applications (2)

Family Applications After (1)

Country Status (6)

Cited By (10)

Families Citing this family (6)

Citations (3)

Family Cites Families (21)

• 1992
  • 1992-07-17 EP EP92306596A patent/EP0524784A1/de active Pending
  • 1992-07-17 JP JP5502891A patent/JPH06509341A/ja active Pending
  • 1992-07-17 AU AU23923/92A patent/AU2392392A/en not_active Abandoned
  • 1992-07-17 CA CA002114009A patent/CA2114009A1/en not_active Abandoned
  • 1992-07-17 WO PCT/US1992/005850 patent/WO1993002081A1/en not_active Application Discontinuation
  • 1992-07-17 EP EP92916482A patent/EP0595989A1/de not_active Ceased
• 1994
  • 1994-01-21 US US08/185,784 patent/US5430032A/en not_active Expired - Fee Related

Patent Citations (3)

Also Published As

Similar Documents

Legal Events